One of the most beautifully written and compelling parts of Seyfried’s exhaustive hypothesis is the idea that metastasis is too complex of a process to be accounted for by random genetic mutation. The idea that many different types of cancer cells would all somehow collect the right genetic mutations that would make them able to enter and exit tissues, evade detection by the immune system, and spread throughout the body seems ludicrous. From the very beginnings of Cancer as a Metabolic Disease, Seyfried begins to question this and show how the process of metastasis involves abilities already present in some macrophages and leukocytes:

Moreover, we found that many metastatic cancers share multiple properties with cells of the myeloid origin (17). these are cells of the immune system such as macrophages and leukocytes. Macrophages and leukocytes are already mesenchymal cells genetically programmed to enter and exit tissues and to survive in hypoxic environments. These are hallmarks of most metastatic tumor cells. (45)

This is a recurring theme in the book, and at points he even notes that “Aichel proposed nearly a century ago that tumor progression involved fusion between leukocytes and somatic cells” (221). And it is this fusion-theory and not genetic mutation that Seyfried advocates as the source for a cancer cell’s ability to metastasize.

“Our results provide the first proof in humans of a theory, proposed in 1911 by a German pathologist, that metastasis can occur when a leukocyte and cancer cell fuse and form a genetic hybrid,” said corresponding author John Pawelek, research faculty in the dermatology department of the Yale School of Medicine. “This could open the way to new therapy targets, but much work needs to be done to determine how fusion occurs, the frequency of such hybrids in human cancers, and the potential role of hybrids in metastasis,” he added.

A model for metastasis resulting from fusion of bone marrow-derived cells is diagramed schematically in Figure 5. While this has largely been verified in animal tumor models and cell culture, evidence for fusion in human cancer has heretofore been lacking. Our findings show for the first time in a human cancer that generation of a metastasis and acquisition of its aberrant genetic patterns resulted from fusion and genomic hybridization between a BMDC and a cancer cell. Depending on the frequency of such events, the findings could have important implications for understanding metastasis, including the origins of tumor initiating cells and the cancer epigenome.

In other words, fusion and NOT genetic mutation account for metastasis.

In contrast to the EMT/MET explanation of metastasis, the macrophage cell fusion explanation of metastasis does not require the induction and reversion of extremely complicated gene regulatory systems. It is only a matter of time before the myeloid fusion hypothesis becomes the dominant explanation of cancer metastasis. (233)

11 Responses to “Cancer as a Metabolic Disease – Update on Metastasis”

It will be interesting to find if the lower insulin levels are in and of themselves the reason for lower observed cancers. Maybe the associated IGF-1 contributes? The ketogenic diet does seem to be a key. Can augmentation with insulin lowering glucophage add to the effect or multiply the effect? My observation and others is that which promotes fertility and frcundity also promotes long healthy lives. Eric

I was wondering the same thing about metformin while I was reading the book…it was really driving me nuts that he wasn’t even considering it.

I would have been well served by a little patience. Seyfried has a section on metformin, in which he writes:

… One side effect of metformin is lactic acidosis. Lactate is produced from glycolysis. glycolysis drives tumor growth. It is therefore possible that metformin could enhance tumor cell glycolysis in some cancer patients. (326)

Seyfried also describes calorie restricted mice who were also given metformin as acting “lethargic and unhealthy”. He suggests this is consistent with lactic acidosis (327).

And lastly,

We also do not think it is good to completely shutdown gluconeogenesis, as glucose is vital for CNS function. We stopped metformin treatment in the tumor-bearing mice under DER (Dietary Energy Restriction) because of unacceptable drug toxicity. When used alone in AL-fed (ad libitinum) mice, however, metformin had no significant influence on brain tumor growth. In other words, our findings in brain tumor-bearing mice treated with metformin were similar to the recent findings of Phoenix and coworkers (227) involving breast cancer. While metformin can be effective in reducing very high blood glucose levels in diabetic and obese patients, I am unsure if metformin will be effective against brain tumor growth in patients. Personally, I would avoid using metformin as a cancer therapy until more extensive preclinical studies are conducted…

The epidemiologic evidence from diabetis is that many cancer types are 30 to 70 percent reduced in metformin users. It does lower blood glucos and blood insulin. It does not stop all gluconeogenesis. It will more likely be more or less effective depending on the cancer. Also it may be more effective the longer it is taken and lower the glucose and insulin levels. It is very effective in animal studies and for some women with fertility issues like high glucose or insulin or PCOS. Generally that which promotes fertility and fecundity is also good for general health and longevity like the ketogenic diet. Eric

There is an old adage of unknown origin (as far as we know) that says that there is no drug that can cure a nutritional disease. The medical community should follow the pathway revealed by the excellent work of Dr. Seyfried and explore the metabolic disruptions of cancer cells and their vulnerabilities.

The mechanism whereby ascorbic acid kills cancer cells without harming normal cells (1) seems not to be of interest to oncology in the United States.

Fascinating stuff!! I think the formation of hybridomas between pre-existing meyloid cells and the transformed fast dividing cells to give rise to metastatic cells is a hugely underestimated possibility. Mind blowing stuff and it would explain a lot of cellular behaviours that it was very difficult to model on the genetic changes alone. We should stand humbled by our own ignorance.
It is the way scientific reserch works and is funded that can explain how we can concentrate so much research effort and generations of scientist can persist on the wrong path for decades.

The article is written for professional health care providers, as is the book.
Dr Seyfried is to be applauded for ensuring his paper was posted at an on-line site that provides free, full-text downloads of its articles.

Personally, I think Seyfried can pull the first 50 or so pages, and the last third of the book and create a new, lay-person-oriented book that covers the history of cancer, history and current context of treatment, standard theory of Cancer as a disease of genetic mutation, Seyfried’s theory of Cancer as a metabolic disease, and his protocol for treating and preventing cancer. Maybe we’ll see something along those lines that’s priced more sensitively…

Hi Michael,
Would appreciate to know how you view Seyfried’s cautions on use of metformin in cancer prevention, specifically in light of other apparently contradictory findings? Reading into his caution, I think that one could actually argue that metformin therapy for diabetics has potential side effect of promoting growth of cancer cells. Or am I taking this too far?

By the way great site with a nice pic of the home page. Applaud your efforts.

What is Seyfrieds conflict of interest?
The drugs and drug research he is connected with conflicts with Glucaphage or the generic metformin? Worth thinking about! The large look at metformin users shows less cancer not the same and not more! Lower glucose and Insulin is associated with better help. WHat is the elevator pitch to show the metformin cancer connection?

Hi Eric:
I did not say “conflict of interest”, and if implied it is not something I meant. To me apparently “conflicting” opinion is better word choice. My comment is related to second half of Michael O’Neill July 1 post quoting Seyfried:
“…While metformin can be effective in reducing very high blood glucose levels in diabetic and obese patients, I am unsure if metformin will be effective against brain tumor growth in patients. Personally, I would avoid using metformin as a cancer therapy until more extensive preclinical studies are conducted… “